FLT3 Inhibitors in Acute Myeloid Leukemia

Khaled el-Shami; Richard M. Stone; B. Douglas Smith


Expert Rev Hematol. 2008;1(2):153-160. 

In This Article

Five-year view

There is a great need for a robust small-animal model to optimize the development of FLT3 inhibitors. A recently generated FLT3-ITD knock-in mouse model showed that the mice developed a myeloproliferative disorder without progression to acute leukemia.[69] It remains to be seen whether this model may be integrated into the development of FLT3, including combination targeting strategies as well as efforts to improve dose, schedule and sequence. The transient nature of the single-agent effect suggests that, unlike imatinib and other small-molecule tyrosine kinase inhibitors, resistance to FLT3 inhibitors emerges during treatment.[70] Clearly, understanding the mechanism(s) of resistance will be useful in the further development of this class of therapeutics. There is accumulating evidence that the main mechanism of resistance to FLT3 inhibitors lies in the acquisition of point mutations that confer resistance to one or more such inhibitors. It has been noted that such mutations occur in the kinase domain after prolonged treatment of FLT3-ITD-positive cells with FLT3 inhibitors, resulting in resistance to PKC412, SU5614 and CEP-701.[71] Additional data point to D835N and Y842H point mutations in the activation loop, resulting in resistance to SU5614.[72] Given the accumulating evidence of the existence of a leukemia stem cell compartment, it will be critical to understand how tryrosine kinase inhibitors interact with the actual leukemia stem cells, and whether such cells can be susceptible to the biological effects of FLT3 inhibitors. With the recent data suggesting that the best consolidation strategy for FLT3-ITD-positive leukemias is a stem cell transplant in first complete remission, strategies using FLT3 inhibitors in maintenance will likely be an active area of investigation with a Phase III CALGB study addressing the role of CEP-701 in maintenance leading the way.

Similar to observations from targeting receptor tyrosine kinases in cancer therapeutics, the relationship between target specificity and clinical efficacy is likely to be better revealed as each clinically studied FLT3 inhibitor demonstrates a varied repertoire of targets and potencies and clinical effect.

Finally, the identification of novel predictive biomarkers such as the 'dose' of the mutant FLT3, homozygosity versus heterozygosity for the mutant alleles might help in selecting AML patients that might derive a clinically meaningful benefit from FLT3 inhibitors.


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